CN1382128A - Substituted benzylthiazolidine-2,4-dione derivatives - Google Patents

Substituted benzylthiazolidine-2,4-dione derivatives Download PDF

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CN1382128A
CN1382128A CN00814707A CN00814707A CN1382128A CN 1382128 A CN1382128 A CN 1382128A CN 00814707 A CN00814707 A CN 00814707A CN 00814707 A CN00814707 A CN 00814707A CN 1382128 A CN1382128 A CN 1382128A
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replace
substituent
hydrate
acceptable salt
pharmacy acceptable
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CN1167691C (en
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宫地弘幸
野村昌弘
棚濑隆宏
村上浩二
角田雅树
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Kyorin Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Substituted benzylthiazolidine-2,4-dione derivatives capable of, as a ligand of human peroxisome proliferator-activated receptor (PPAR), enhancing the transcriptional activity of the receptor and showing effects of lowering blood sugar level and lowering lipid level; and a process for producing the same. Novel substituted benzamide derivatives represented by general formula (1), pharmaceutically acceptable salts thereof, hydrates and manufacture method thereof wherein A represents optionally substituted phenyl, optionally substituted phenoxy or optionally substituted benzyloxy.

Description

The benzyl thiazolidine-2 that replaces, the 4-derovatives
Technical field
The present invention relates to effectively to treat and/or prevent metabolism diseases such as diabetes and hyperlipidaemia as the agonist of peroxisome proliferator-activated receptor (intranuclear receptor) (abbreviating PPAR as), especially as the benzyl thiazolidine-2 of the replacement of people PPAR agonist, 4-derovatives and additive salt thereof, their manufacture method and the medical composition that contains these compounds.
Background technology
Peroxisome proliferator-activated receptor (abbreviating PPAR as) is and the identical ligand-dependent type transcription factors that belong to the intranuclear receptor superfamily such as steroid receptor, retinoid acceptor and thryoid receptor.At present in people and various animal species, the different three kinds of isotypes (α type, β (or δ) type, γ type) (Proc.Natl.Acad.Sci.1992,89,4653) of tissue distribution have been identified.Wherein, PPAR α is distributed in fatty acid metabolism the ability high liver and kidney, and high expression level (Endocrinology, 1995,137,354) is especially arranged in liver.Carry relevant gene (for example acyl-CoA synthetic enzyme, fatty acid binding protein matter and lipoprotein lipase) and the lipophorin (AI relevant in its energy positive regulation or negative control and fatty acid metabolism and the born of the same parents with the metabolism of cholesterol and neutral lipid; AII, CIII) expression of gene.PPAR β is that generally express in each tissue in vivo at the center with the neurocyte.At present, not clear about the physiologic meaning of PPAR β.PPAR γ high expression level in adipocyte is with adipocyte differentiation relevant (J.Lipid.Res., 1996,37,907).Like this, the various isotypes of PPAR play specific function in specific organ and tissue.
In addition, it is reported, the mouse that PPAR α rejects presents high neutral fat mass formed by blood stasis with the age increase, the white adipose cell increases to main and fat (the J.Biol.Chem. that becomes, 1998,273,29577), the activation of this strong hint PPAR α is relevant with the reduction effect of blood fat (cholesterol and neutral lipid).
On the one hand, extensively adopted fiber-like class (Off イ Block ラ one ト) medicine and statin class medicine to treat hyperlipidemia in the past.Yet fiber-like class medicine reduces a little less than the effect of cholesterol, and on the other hand, statin class medicine reduces a little less than the effect of free fatty acids and triglyceride level.And, it is reported that fiber-like class medicine has various side effects such as stomach and intestine injury, eruption, headache, liver function damage, impaired renal function and gallbladdergallstonecholetithiasis, thinks that its reason is that fiber-like class medicine shows pharmacological action widely.
On the other hand, confirmation form reveals lowering blood glucose, a series of thiazolidine-2s of hyperinsulinemia improvement effect, main born of the same parents' internal object protein of 4-derovatives Tuo Lite ancestor (ト ロ グ リ ゾ Application), Pai Lite ancestor (ピ オ グ リ ゾ Application) and Luo Xite ancestor (ロ ジ グ リ ゾ Application) (type ii diabetes (non insulin dependent diabetes) curative) is PPAR γ, these medicines make the transcriptional activity of PPAR γ strengthen (Endocrinology, 1996,137,4189, Cell, 1995,83,803, Cell, 1995,83,813).Therefore, make the transcriptional activity enhanced PPAR γ activator (agonist) of PPAR γ very important as the lowering blood glucose medicine.
Consider these transcription factors that are called PPAR for the function of adipocyte and with regulate carbohydrate metabolism relevant with lipid metabolism mechanism do the time spent, if can produce as the direct combination of PPAR, especially people PPAR part and make people PPAR activatory compound, estimate to have medicinal use so by the compound that very specific mechanism shows the lowering blood glucose effect and/or reduces lipid (cholesterol and neutral lipid) effect in the blood.
It is reported,, remove the arachidonic metabolite LTB of compound that PPAR α is had affinity as the part of PPAR α 4Outward, also have by the HETE (hydroxyeicosatetraenoic acid) of cytochrome P-450 oxidation generation and the quasi-eicosane alcohol (エ イ コ サ ノ イ De) of HEPE (acid of hydroxy-20 carbon pentaene) group, especially 8-HETE, 8-HEPE (Proc.Natl.Acad.Sci.94,312).Yet these endogenic unsaturated fatty acid derivatives are in metabolism and chemically unstable, can not be made for medicine.
In addition, for the Tuo Lite ancestor, idol has its report to the severe side effect of liver, is therefore just requiring to develop effective and safe type ii diabetes curative.
Now, as with the benzyl thiazolidine-2 of replacement of the present invention, the compound of 4-derovatives structural similitude, the known thiazolidine-2 that has among the clear 55-22636 of Japanese Patent Application Publication communique, clear 60-51189, clear 61-85372, clear 61-286376, flat 1-131169, flat 2-83384, flat 5-213913, flat 8-333355, flat 9-48771, flat 9-169746, european patent application publication 0441605, the WO92/07839 etc., the 4-diketone.Yet all these compounds all are structurally different with The compounds of this invention thiazolidine-2s, the 4-derovatives.
Patent about report PPAR α agonism has WO97/25042, WO97/36579 etc., yet all the structure with The compounds of this invention is different for all these, and the intensity of the transcription activating effect of PPAR α is also also unsatisfactory.
Hyperlipidaemia and diabetes all are arteriosclerotic Hazard Factor, therefore from the viewpoint of prevention of arterial sclerosis disease, especially coronary sclerosis, wish to develop effective and safe metabolic disease curative clinically.
The announcement of invention
The present inventor is a purpose to produce as new medicine on effective, the safe and structure of metabolic disease curative, be conceived to people PPAR and done deep research for the specific effect of lipid metabolism and adipocyte differentiation etc., found that, the benzyl thiazolidine-2 of the replacement of following general formula (1) expression, the 4-derovatives has outstanding PPAR transcriptional activation, and show the effect of lowering blood glucose and the effect of minimizing lipid, thereby finished the present invention.
That is, the present invention relates to the benzyl thiazolidine-2 of the replacement of general formula (1) expression, 4-derovatives and pharmacy acceptable salt thereof and its hydrate: In the formula: A represents not replace or substituent phenyl is arranged, do not replace or have substituent phenoxy group, do not replace or have substituent benzyloxy.
The salt of the compound of formula of of the present invention (1) expression is used always, can be pharmacy acceptable salts such as metal-salt such as an alkali metal salt (as sodium salt, sylvite etc.), alkaline earth salt (as calcium salt, magnesium salts etc.), aluminium salt.
In addition, contain sometimes based on thiazolidine-2 in the compound of formula of of the present invention (1) expression, the optical isomer of 4-diketone loop section, but all these isomer and composition thereof include within the scope of the present invention.
In addition, in the compound of general formula (1) expression, think there are various tautomers that it is for example shown in the following formula.
Figure A0081470700062
In the formula: A represents not replace or substituent phenyl is arranged, do not replace or have substituent phenoxy group, do not replace or have substituent benzyloxy.In above-mentioned general formula (1), these isomer and their mixture include within the scope of the present invention.
According to the present invention, for example available following method of the compound of above-mentioned general formula (1) makes (scheme 1).
Figure A0081470700063
Scheme 1 promptly, the compound of general formula (1) expression can react that (step 1) makes by the compound that the compound (2) and the general formula (3) of known (the open flat 8-333355 of communique of Japanese Patent) are represented
Figure A0081470700064
A represents not replace or substituent phenyl is arranged, do not replace or have substituent phenoxy group, do not replace or have substituent benzyloxy in the formula.
Step 1 can be constant or be converted into reactive derivatives and carry out by keeping carboxyl.
As " reactive derivatives of carboxyl ", chloride of acid, acid bromide, acid anhydrides, carbonylic imidazole etc. are for example arranged.Under the occasion that adopts reactive derivatives, reaction can be such as methylene dichloride, chloroform, diox, N, in the dinethylformamide equal solvent, carrying out in the presence of the alkali of alkaline carbonates such as alkali metal hydroxides such as alkalimetal hydrides such as for example sodium hydride, sodium hydroxide, yellow soda ash or organic basess such as pyridine, triethylamine or not.
Keeping under the constant situation of reacting of carboxylic acid, reaction can in the dinethylformamide equal solvent, in the presence of condensing agent, in the alkali existence or not, be carried out in the additive existence or not at methylene dichloride, chloroform, diox, N.
As condensing agent, for example be dicyclohexylcarbodiimide, 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride, diethyl phosphorocyanidate, diphenyl phosphate azide, carbonyl dimidazoles etc.Alkaline carbonate or organic basess such as pyridine, triethylamine such as alkali metal hydroxide, salt of wormwood such as sodium hydroxide are for example arranged as alkali.As additive, N-hydroxybenzotriazole, N-hydroxy-succinamide, 3 are for example arranged, 4-dihydro-3-hydroxyl-4-oxo-1,2,3-phentriazine etc.Temperature of reaction is-20 ℃ to 100 ℃, and preferable can react under 50 ℃ at 0 ℃.
The form of medication of new compound of the present invention for example is with oral administrations such as tablet, capsule, granule, powder agent, inhalation, syrup, perhaps carries out administered parenterally with injection, suppository.
The best way that carries out an invention
Below object lesson according to the present invention is described, yet the present invention is not limited to these examples.
(embodiment 1)
N-[(4-benzyloxy phenyl) methyl]-5-[(2,4-dioxo thiazolidine-5-yl) methyl]-the 2-methoxy benzamide
With 5-[(2,4-dioxo thiazolidine-5-yl) methyl]-O-Anisic Acid (422 milligrams, 1.50 mmoles), triethylamine (0.523 milliliter, 3.75 mmoles) and methylene dichloride (5 milliliters) mix, ice-cooled stirring adds Vinyl chloroformate (0.158 milliliter, 1.50 mmoles) down.Ice-cooled stirring added 4-(benzyloxy) the benzyl amine (319 milligrams, 1.50 mmoles) that is dissolved in 2 milliliters of methylene dichloride after 10 minutes.Stir standing over night after 2 hours under the room temperature.Reaction solution washes the back with water and also concentrates with anhydrous sodium sulfate drying.Residue is dissolved in 40 ml waters, transfers to acidity with 10% hydrochloric acid, stirs 30 minutes.The crystallization that leaching is separated out, dry back recrystallization in the mixed solvent of second alcohol and water obtains 549 milligrams of (77%) colourless powder shape title compounds.
Fusing point 131.0-132.5 ℃;
Mass analysis value: m/z 476 (M +)
Ultimate analysis value (%) C 26H 24N 2O 5S:
Calculated value (%): C, 65.53; H, 5.08; N, 5.88. measured value (%): C, 65.68; H, 5.08; N, 5.91. (embodiment 2-3) is the same with embodiment 1, obtains following compound.(embodiment 2) N-[(xenyl-4-yl) methyl]-5-[(2,4-dioxo thiazolidine-5-yl) methyl]-170.5-172.0 ℃ of 2-methoxy benzamide fusing point; Mass analysis value: m/z 446 (M +) ultimate analysis value (%) C 25H 22N 2O 4S: calculated value (%): C, 67.25; H, 4.97; N, 6.27. measured value (%): C, 67.29; H, 4.99; N, 6.21. (embodiment 3) N-[(4-Phenoxyphenyl) methyl]-5-[(2,4-dioxo thiazolidine-5-yl) methyl]-87.0-89.0 ℃ of 2-methoxy benzamide fusing point; Mass analysis value: m/z 462 (M +) ultimate analysis value (%) C 25H 22N 2O 5S1/5H 2O: calculated value (%): C, 64.42; H, 4.84; N, 6.01. measured value (%): C, 64.17; H, 4.81; N, 6.03. (embodiment 4-14) is the same with embodiment 1, obtains the compound in the table 1.
(table 1)
Mass analysis value embodiment A fusing point (℃) chemical formula ultimate analysis (%)
(m/z) amorphous 492 (M) of 4 4-OPh (2-OMe) +C 26H 24N 2O 6S calculated value: C63.40, H4.91, N5.69
Measured value: C63.05, H4.95, amorphous 492 (M) of N5.57 5 4-OPh (3-OMe) +C 26H 24N 2O 6S calculated value: C63.40, H4.91, N5.69
Measured value: C63.13, H4.95, amorphous 492 (M) of N5.54 6 4-OPh (4-OMe) +C 26H 24N 2O 6S calculated value: C63.40, H4.91, N5.69
Measured value: C63.05, H4.99, N5.54 7 4-OPh (3-Me) 154.0-156.0 476 (M) +C 26H 24N 2O 5S calculated value: C65.53, H5.08, N5.88
Measured value: C65.29, H5.16, N5.79 8 4-OPh (4-Me) 146.0-147.0 476 (M) +C 26H 24N 2O 5S calculated value: C65.53, H5.08, N5.88
Measured value: C65.20, H5.10, N5.87 9 4-Ph (4-Cl) 200.0-202.0 480 (M) +C 25H 21ClN 2O 4S calculated value: C61.85, H4.46, N5.77
1/4H 2O measured value: C61.92, H4.35, N5.74 10 4-Ph (4-OMe) 201.0-202.0 476 (M) +C 26H 24N 2O 5S calculated value: C64.92, H5.13, N5.82
1/4H 2O measured value: C65.02, H5.12, N5.81 11 4-OCH 2Ph (4-Cl) 158.0-160.0 510 (M) +C 26H 23ClN 2O 5S calculated value: C61.11, H4.54, N5.48
Measured value: C61.22, H4.53, N5.46 12 4-OCH 2Ph (4-Me) 181.0-183.0 490 (M) +C 27H 26N 2O 5S calculated value: C65.50, H5.39, N5.66
1/4H 2O measured value: C65.37, H5.28, N5.57 13 4-Ph (4-Me) 190.0-192.0 460 (M) +C 26H 24N 2O 4S calculated value: C67.81, H5.25, N6.08
Measured value: C67.56, H5.22, N6.02
＜biological activity 〉
(test example 1)
Transcriptional activation test for peroxisome proliferator activated acceptor α and γ
Removed in the Ham ' s F-12 substratum of foetal calf serum of free fatty acids and cultivated Chinese hamster ovary celI containing 10%, under the serum-free state, utilize amine fat transfection agents (lipofectamine) with receptor plasmid and report plasmid (STRATAGENE company) thereof and as beta-galactosidase enzymes plasmid (Promega company) cotransfection of internal standard in this Chinese hamster ovary celI, wherein said receptor plasmid is expressed the ligand binding domains (Biochemistry of yeast transcription factor DNA binding domains and people PPAR α and γ, 1993,32,5598) fusion rotein.Subsequently, (control drug of PPAR γ is Tuo Lite ancestor and Pai Lite ancestor with test compounds and control compound, the control drug of PPAR α is dissolved among the DMSO for (8S)-HETE), with containing the ultimate density that the 10% Ham ' s F-12 substratum of removing the foetal calf serum of free fatty acids transfers to DMSO is 0.01%, cultivates.Cultivate after 24 hours, measure CAT activity and betagalactosidase activity.
The result is presented in the table 2.These results show that compound of the present invention has potent transcriptional activation for human peroxisome proliferator-activated receptor α and γ.
Table 2
Transcriptional activation
Embodiment PPAR α PPAR γ
EC 50(micromoles per liter) EC 50(micromoles per liter)
1 0.44 -
2 0.63 6.8
3 0.24 0.24
Tuo Lite ancestor-1.15
Pai Lite ancestor-0.72
(8S)-HETE 1.30 -
Utilize possibility on the industry
According to The above results, the benzylthiazolidine-2,4-dione derivatives of replacement of the present invention is to have outstanding people The noval chemical compound class of PPAR transcriptional activation.
To the fact that people PPAR has agonist activity, can say that they are can be used as from these compounds of the present invention The active compound of above-mentioned medicine for treating diabetes and/or hyperlipidemia curative.

Claims (10)

1. use the benzyl thiazolidine-2 of the replacement of general formula (1) expression, 4-derovatives and pharmacy acceptable salt thereof and hydrate thereof, In the formula, A represents not replace or substituent phenyl is arranged, do not replace or have substituent phenoxy group, do not replace or have substituent benzyloxy.
2. the benzyl thiazolidine-2 of replacement according to claim 1,4-derovatives and pharmacy acceptable salt thereof and hydrate thereof, wherein A does not replace or substituent phenyl is arranged.
3. the benzyl thiazolidine-2 of replacement according to claim 1,4-derovatives and pharmacy acceptable salt thereof and hydrate thereof, wherein A does not replace or substituent phenoxy group is arranged.
4. the benzyl thiazolidine-2 of replacement according to claim 1,4-derovatives and pharmacy acceptable salt thereof and hydrate thereof, wherein A does not replace or substituent benzyloxy is arranged.
5. compound according to claim 1 and pharmacy acceptable salt and hydrate thereof, wherein this compound is a N-[(4-benzyloxy phenyl) methyl]-5-[(2,4-dioxo thiazolidine-5-yl) methyl]-the 2-methoxy benzamide.
6. compound according to claim 1 and pharmacy acceptable salt and hydrate thereof, wherein this compound is the N-[(4-Phenoxyphenyl) methyl]-5-[(2,4-dioxo thiazolidine-5-yl) methyl]-the 2-methoxy benzamide.
7. compound according to claim 1 and pharmacy acceptable salt and hydrate thereof, wherein this compound is N-[(xenyl-4-yl) methyl]-5-[(2,4-dioxo thiazolidine-5-yl) methyl]-the 2-methoxy benzamide.
8. the medicine of a lowering blood glucose, it contains the benzyl thiazolidine-2 of the replacement of at least a above general formula (1) expression, and 4-derovatives, its pharmacy acceptable salt and hydrate thereof be as effective constituent,
Figure A0081470700022
In the formula, A represents not replace or substituent phenyl is arranged, do not replace or have substituent phenoxy group, do not replace or have substituent benzyloxy.
9. medicine that reduces lipid in the blood, it contains the benzyl thiazolidine-2 of the replacement of at least a above general formula (1) expression, and 4-derovatives, its pharmacy acceptable salt and hydrate thereof be as effective constituent, In the formula, A represents not replace or substituent phenyl is arranged, do not replace or have substituent phenoxy group, do not replace or have substituent benzyloxy.
10. the agonist of a human peroxisome proliferator-activated receptor, it contains the benzyl thiazolidine-2 of the replacement of at least a above general formula (1) expression, and 4-derovatives, its pharmacy acceptable salt and hydrate thereof be as effective constituent,
Figure A0081470700031
In the formula, A represents not replace or substituent phenyl is arranged, do not replace or have substituent phenoxy group, do not replace or have substituent benzyloxy.
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BRPI0515015A (en) * 2004-08-11 2008-07-01 Kyorin Seiyaku Kk cyclic aminobenzoic acid derivative; medicine; ppar (alpha) agonist; ppar (alpha) double agonist, y; ppar double agonist (alpha), (delta); par modulator; lipid agent; prophylactic or therapeutic agent comprising at least one of the pharmaceutically acceptable cyclic derivatives of aminobenzoic acid or salt thereof
CN101189231B (en) * 2005-03-23 2011-05-18 杏林制药株式会社 Novel cyclic aminophenylalkanoic acid derivative

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